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In the Clinic-Multiple Sclerosis
Siponimod Slows Disability Progression in Secondary Progressive MS, Modestly



DR. ROBERT J. FOX: “Progressive MS probably begins much earlier than we currently think. Should we be using these therapies earlier? Probably, but we dont know how early.”

In a phase 3 trial, siponimod significantly slowed progression of secondary progressive multiple sclerosis, but commentators noted the effect was modest.

Siponimod slows progression of disability in secondary progressive multiple sclerosis (SPMS), according to a phase 3 double-blind, placebo-controlled trial published in the March 22 edition of The Lancet.

During a mean treatment of 18 months, 26 percent of patients taking the drug reached the primary endpoint of three-month confirmed disability progression, versus 32 percent of those taking placebo.

“This is a significant, though modest, reduction in risk of progression,” commented Mitchell Wallin, MD, MPH, director of the Veterans Administration MS Center of Excellence East in Baltimore, MD, who was not involved in the study. Results of the trial were previously reported at the 2017 Annual Meeting of the American Academy of Neurology and at the European Committee for Treatment and Research in MS.

Like fingolimod, siponimod is a modulator of sphingoside-1-phosphate (S1P) receptors. But while fingolimod interferes with the function of all five types of the receptor, siponimod selectively modulates types 1 and 5. Type 1 is found on peripheral lymphoid tissue, where it promotes egress of lymphocytes, while type 5 is concentrated in brain white matter.

While siponimod crosses the blood-brain barrier, a full understanding of its mechanism, especially in the brain, is still elusive, according to study co-author Robert J. Fox, MD, FAAN, staff neurologist at the Mellen Center for Multiple Sclerosis and vice chair for research of the Neurological Institute of the Cleveland Clinic.

In MS, “there are two processes going on, in parallel and to different degrees,” Dr. Fox said. Early on, infiltrative inflammation predominates, characterized clinically by relapses and remission. “Our current therapies are very good at stopping that,” he said. Later on, he explained, degeneration becomes more prominent, which is thought to manifest clinically as secondary progression. “Unfortunately, we don't have any standard therapies for progressive MS,” he noted

Mitoxantrone is approved for secondary progression but is associated with significant cardiac toxicity. Fingolimod, approved for relapsing-remitting MS, recently failed to show an effect on progression. Other drugs, including ocrelizumab and natalizumab, are currently in clinical trials.


To test siponimod's ability to slow progression, Dr. Fox and colleagues at 292 clinical centers in Europe and North America randomized 1651 patients 2:1 to siponimod, taken orally at 2 mg/day, or placebo. The primary endpoint was time to three-month confirmed disease progression (CDP), defined as a 1.0 point increase in Expanded Disability Status Scale (EDSS) score for those with moderate disability, or a 0.5 point increase for those with more significant disability at baseline. Upon reaching the endpoint, patients could switch to open-label siponimod or stop treatment. The trial was sponsored by the drug's maker, Novartis, and Novartis employees contributed to the study throughout.

The median time on study drug was 18 months. Twenty-six percent of patients receiving siponimod, versus 32 percent on placebo, developed sustained disability, for a hazard ratio of 0.79 favoring siponimod, and a relative risk reduction of 21 percent (p=0.13).

There was no treatment benefit on the timed 25-foot walk test. Multiple imaging endpoints favored siponimod, including a reduction from baseline in T2 lesion volume, and freedom from gadolinium-enhancing lesions. Patients on siponimod had less decline in brain volume between months 12 and 24 than patients on placebo (-0.50% versus -0.65%, p=0.0002).

“Can we slow the progression of disability with this drug? Yes, we can,” Dr. Fox said, but not dramatically, he added. “What patients want is a restoration of function, and none of the drugs we are currently studying, including this one, does that.”

The patients who gained the most benefit from treatment were those with relapses in the two years before enrollment, those with rapid progression, and those with better function at baseline.

The rate of adverse events was similar between the two treatment arms. Events consistent with S1P modulation that were more common in those on active treatment included bradycardia after initiation of therapy (4 percent versus 3 percent), hypertension (12 percent versus 9 percent), and lymphopenia (1 percent versus 0 percent).

“As a practicing neurologist, I hope this therapy comes out as quickly as possible, because there is a big unmet need in progressive MS,” Dr. Fox said. Novartis, the sponsor of the trial, plans to submit these results to the Food and Drug Administration, for marketing approval in early 2018, according to the company website.

If it is approved, an important unanswered question will be when to begin treatment. “Progressive MS probably begins much earlier than we currently think,” Dr. Fox said. “Should we be using these therapies earlier? Probably, but we don't know how early.”


Dr. Wallin, of the Veterans Administration, who is also associate professor of neurology at Georgetown University and the University of Maryland School of Medicine, said that he viewed the results with “guarded optimism.”

The trial population was typical of the secondary progressive population seen in clinical practice but older than in most trials, with a small proportion with inflammatory activity at baseline, he said.

“The imaging findings were pretty robust,” he added, although these probably reflect the anti-inflammatory action of siponimod, he said.

The trial was relatively short, he noted, with an average treatment time of only 18 months, less than most other secondary progressive treatment trials. That, combined with the “modest” effect on progression, would make a second trial advisable.

John Corboy, MD, FAAN, professor and vice chair of neurology at the University of Colorado Anschutz Medical Campus, who was a site principal investigator on the trial, commented that although the patient group was more representative of the target treatment population than in most secondary progressive trials, “they are still relatively young,” with a median age of 48.

Additionally, he noted, the characteristics associated with the greatest benefit — higher function, more rapid progression, and relapses close to baseline —“are all consistent with greater inflammatory disease activity being a predictor of response, as has been seen in essentially every study of MS ever done,” with the exception of the fingolimod trial for primary progressive MS, which was negative.

So while the trial “was extremely well done,” and while there appears to be a benefit in secondary progressive MS for some patients, he said, “this study explicitly does not suggest that use in older patients with no recent inflammatory disease activity is warranted.” While the benefit on brain atrophy was gratifying, he noted it was smaller than that reported with other drugs or supplements in even older patients with progressive MS, including ibudilast, simvastatin, and alphalipoic acid.

DISCLOSURES: Dr. Fox reports personal fees from Actelion, Biogen, Genentechm Novartis, Teva, Malinkckrodt, and Xenoport; grants from Novartis; and other support from Biogen (clinical trial contracts).


• Kappos L, Bar-Or A, Cree BAC, et al; for the EXPAND Clinical Investigators. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study Lancet 2018; pii: S0140–6736(18)30475–30476.